Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation

肾单位祖细胞自我更新和分化的调节

基本信息

批准号：
8908006
负责人：
MICHAEL I RAUCHMAN
金额：
$ 32.95万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-07 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8908006
关键词：
Agonist Binding Binding Sites Biochemical Cell Differentiation process Cells ChIP-seq Childhood Chromatin Remodeling Factor Chronic Kidney Failure Complement Complex Congenital Abnormality Deacetylase Development Differentiation Inhibitor Elements Embryo End stage renal failure Endowment Enhancers Ensure Epigenetic Process Epithelial Epithelial Cells Equilibrium Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetically Engineered Mouse Genomics Goals Health Human Human Genetics Hypertension In Vitro Injury Kidney Kidney Diseases Kidney Failure Knock-in Mouse Knowledge Life Maintenance Maps Mesenchyme Messenger RNA Modeling Molecular Mus Mutant Strains Mice Mutate Natural regeneration Nephrons Nucleosomes Organ Organ Culture Techniques Output Patients Play Population Regulation Renal function Research Risk Signal Transduction Sorting - Cell Movement Stem cells Syndrome Testing Therapeutic Transcriptional Regulation Tubular formation Undifferentiated Ureter Vesicle Work epithelial to mesenchymal transition exhaustion genome-wide analysis in vivo inhibitor/antagonist insight mutant nephrogenesis novel precursor cell premature prevent progenitor repaired research study response self-renewal stemness transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of the proposed work is to determine how the Sall1 transcription factor and its associated chromatin remodeling complexes control gene regulation to generate a normal endowment of nephrons. This will illuminate mechanisms that underlie human genetic syndromes and common sporadic birth defects, such as renal hypoplasia (small kidneys with reduced numbers of nephrons), which result in kidney failure. Formation of the proper complement of nephrons requires a balance between expansion of multi-potent renal progenitor cells and differentiation. Genetic deficiency of Sall1 alters gene expression in the developing kidney, accelerating nephron differentiation leading to a depletion of nephron progenitor cells and renal hypoplasia. These uncommitted nephron precursors, termed cap mesenchyme, must respond to canonical Wnt/ss-catenin signals by either undergoing self-renewal or mesenchymal-to-epithelial transition to form most tubular segments of the nephron. The transcriptional mechanisms that control these opposing responses of the cap mesenchyme are not known, but current evidence argues that Sall1 is pivotal in this critical developmental decision. Our recent studies provide evidence for a novel paradigm. We propose that Sall1 cooperates with the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex, to determine nephron progenitor cell fate by regulating the transcriptional output in response to Wnt/ss-catenin. This application will test key predictions of this model using a combination of genetic, genomic, and biochemical approaches. Six2 is an inhibitor of nephron differentiation. In Aim 1, we will determine if Sall1 directly up-regulates Six2 expression in cap mesenchyme to restrain differentiation of progenitor cells. Expression of Wnt9b, the main differentiation signal, is increased in Sall1 mutants. We will determine if the combination of increased Wnt9b and reduced Six2 expression are sufficient to cause accelerated nephron formation, and exhaustion of self-renewing progenitor cells. Aim 2 will determine how Sall1 and NuRD control the transcriptional output in nephron progenitor cells to determine whether the uncommitted precursor cells undergo self-renewal or initiate nephron differentiation. The mechanistic insights gained from these studies will advance efforts to propagate nephron progenitors in vitro and/or promote regeneration of mature tubular epithelial cells in order to correct nephron deficits.

描述（由申请人提供）：拟议工作的长期目标是确定SALL1转录因子及其相关的染色质重塑络合物如何控制基因调节以产生正常的肾脏赋。这将阐明人类遗传综合征和常见零星先天缺陷的基础的机制，例如肾功能低下（肾单位数量减少），从而导致肾衰竭。正确补体的形成需要在多功能肾脏祖细胞的扩展与分化之间保持平衡。 SALL1的遗传缺乏改变了发育中的肾脏中的基因表达，加速了肾分化，导致肾祖细胞和肾功能低下的耗竭。这些未拨打的肾单位前体（称为盖帽间充质）必须通过进行自我更新或间质对上皮到上皮过渡以形成肾单位的大多数管状段来响应规范的Wnt/SS-catenin信号。尚不清楚控制帽间充质的这些相反反应的转录机制，但目前的证据表明，在这个关键的发展决策中，SALL1是关键的。我们最近的研究为新型范式提供了证据。我们提出SALL1与核小体重塑和脱乙酰基酶（NURD）染色质重塑复合物合作，通过调节对Wnt/SS-Catenin的转录输出来确定肾单位祖细胞的命运。此应用程序将测试使用遗传，基因组和生化方法的组合对该模型的关键预测。 Six2是肾单位分化的抑制剂。在AIM 1中，我们将确定SALL1是否直接上调帽间充质中的六个表达以限制祖细胞的分化。在SALL1突变体中，Wnt9b的表达是主要分化信号。我们将确定增加的Wnt9b和降低的六个表达的组合是否足以引起加速的肾单位形成以及自我更新祖细胞的耗尽。 AIM 2将确定SALL1和NURD如何控制肾单位祖细胞中的转录输出，以确定未承诺的前体细胞是否经历自我更新或启动肾单位分化。从这些研究中获得的机械洞察力将促进体外和/或促进成熟管状上皮细胞再生以纠正肾脏缺陷的努力。